Beta-lactam antibiotics are the most widely used antibacterial drugs in the treatment of bacterial infections. As a fierce fight back, bacteria produce enzymes called β-lactamases, which break down the β-lactams, leading to a broad-spectrum resistance to this class of antibiotics. The emergence and spreading of β-lactamases constitutes an enormous threat to public health globally.1-3 
Based on the unique enzymatic mechanisms, β-lactamases can be functionally classified to two major types, i.e. serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs) with the former employing a serine as a nucleophile and the latter using zinc ions to breakdown β-lactam ring.4 MBLs are considered as the more injurious β-lactamases conferring a broad-spectrum of resistance to β-lactam antibiotics due to their unique enzymatic mechanism.5-7 This is largely due to the followings: (1) resistant determinants of MBLs are often encoded on mobile genetic elements and could easily spread among/across a variety of bacterial species by horizontal gene transfer. The predominant MBLs producers, Enterobacteriaceae including Escherichia spp., Klebsiella spp., Pseudomonas spp., Acinetobacter spp. and Enterococcus. spps., could be easily found in community and even health-care context, and spread among people by hand carriage, food and water.8-11 (2) MBLs have strong β-lactamase activity and are able to hydrolyze or inactivate the most commonly used β-lactam antibiotics, such as cephalosporins and carbapenems. Furthermore most MBLs producing enterobacterial strains are able to co-express other types of resistance genes including those encoding other β-lactamases (AmpC, ESBL, OXA-48 and KPC) and resistance determinants for other antibiotics including fluoroquinolones (qnrA6 and qnrB1), aminoglycosides (armA, rmtA and rmtC), acrolides (ereC), rifampicin (arr-2) and sulfonamide (sul-2).4,12,13 The latest example of MBLs is New Delhi metallo-β lactamase-1 (“NDM-1”). In 2009, a Swedish patient was firstly reported to be infected by NDM-1 producing Klebsiella pneumoniae with resistance to multiple antibiotics including all carbapenems upon the return from India.9 Ever since, NDM-1 has been spread to all inhabited continents wherein Indian subcontinent and China emerge as the two biggest reservoirs, and therefore NDM-s is often regarded as the notorious “superbug” in mass medium.14-23 However, there appears no effective treatment for the infection caused by NDM-1.
There is a lack of inhibitor specifically targeting MBLs available clinically up to date. MBLs are considered more menacing than SBLs owing to the following two aspects: (1) the architectures of active sites of MBLs vary greatly among microorganisms. Thus it remains to be a great challenge to design an inhibitor against all MBLs among different bacteria. (2) Unlike SBLs, MBLs have no or few stable reaction intermediates, which immensely increase the difficulty in copying the inhibition mode of SBLs inhibitor, such as clavulanic acid.7,12 
Till now, considerable efforts have been made for the development of MBL inhibitors. A representative MBL inhibitor is Aspergillomarasmine A (AMA) reported in Nature, 2014, which is effective against MBLs (mainly for NDM-1 and VIM-2) among a variety of gram-negative bacteria and exerts good in vivo efficacy against K. pneumonia (NDM+).28 Another example is a rhodanine-derived thioenolate showing a potent broad-spectrum activity against MBLs. The thioenolate is found to bind VIM-2 via di-zinc chelation by crystallography.29 Since then, quite a few MBL inhibitors began to emerge and make progress in this area, but their in vivo efficacies have not been proved yet. Above instances mirror the conventional way to deal with MBLs, i.e. designing inhibitors which are able to coordinate to or chelate Zn(II) in the active sites, such as carboxylic acids and thiol-containing compounds. But such a strategy usually suffer from relatively poor selectivity and low efficacy and is unlikely to develop a wide-spectrum of MBL inhibitors, not to mention the hidden worry of the generation of resistance to those organic inhibitors by microorganisms. Furthermore, though some FDA-approved drugs, such as DL-captopril, glutathione and 2,3-dimercaprol,30 have been used in the studies, no clinically available MBL inhibitor has been approved yet. Therefore, there appears to be lack of developments of the relevant MBLs inhibitors.